JP2012528804A - Method for producing drug-loaded emulsion - Google Patents
Method for producing drug-loaded emulsion Download PDFInfo
- Publication number
- JP2012528804A JP2012528804A JP2012513464A JP2012513464A JP2012528804A JP 2012528804 A JP2012528804 A JP 2012528804A JP 2012513464 A JP2012513464 A JP 2012513464A JP 2012513464 A JP2012513464 A JP 2012513464A JP 2012528804 A JP2012528804 A JP 2012528804A
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- Prior art keywords
- oil
- drug
- emulsion
- water
- group
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- 239000000839 emulsion Substances 0.000 title claims abstract description 148
- 229940079593 drug Drugs 0.000 title claims abstract description 142
- 239000003814 drug Substances 0.000 title claims abstract description 142
- 238000004519 manufacturing process Methods 0.000 title claims abstract description 30
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 100
- 239000004480 active ingredient Substances 0.000 claims abstract description 10
- 239000012528 membrane Substances 0.000 claims abstract description 5
- 239000003921 oil Substances 0.000 claims description 82
- 235000019198 oils Nutrition 0.000 claims description 82
- 239000012071 phase Substances 0.000 claims description 69
- 238000000034 method Methods 0.000 claims description 59
- 239000008346 aqueous phase Substances 0.000 claims description 51
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 48
- 239000000203 mixture Substances 0.000 claims description 42
- 239000002245 particle Substances 0.000 claims description 32
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- 239000008344 egg yolk phospholipid Substances 0.000 claims description 22
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- 239000003963 antioxidant agent Substances 0.000 claims description 16
- 235000006708 antioxidants Nutrition 0.000 claims description 16
- 230000003078 antioxidant effect Effects 0.000 claims description 15
- 238000000265 homogenisation Methods 0.000 claims description 13
- 239000002904 solvent Substances 0.000 claims description 13
- -1 polyoxyethylene Polymers 0.000 claims description 11
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- BCKXLBQYZLBQEK-KVVVOXFISA-M Sodium oleate Chemical compound [Na+].CCCCCCCC\C=C/CCCCCCCC([O-])=O BCKXLBQYZLBQEK-KVVVOXFISA-M 0.000 claims description 10
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- 238000004945 emulsification Methods 0.000 claims description 9
- 238000005192 partition Methods 0.000 claims description 9
- 229920003171 Poly (ethylene oxide) Polymers 0.000 claims description 8
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 8
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- 238000002156 mixing Methods 0.000 claims description 7
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- 239000000243 solution Substances 0.000 claims description 7
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- 239000006185 dispersion Substances 0.000 claims description 6
- QXJSBBXBKPUZAA-UHFFFAOYSA-N isooleic acid Natural products CCCCCCCC=CCCCCCCCCC(O)=O QXJSBBXBKPUZAA-UHFFFAOYSA-N 0.000 claims description 6
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- 150000003904 phospholipids Chemical class 0.000 claims description 6
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- QFOHBWFCKVYLES-UHFFFAOYSA-N Butylparaben Chemical compound CCCCOC(=O)C1=CC=C(O)C=C1 QFOHBWFCKVYLES-UHFFFAOYSA-N 0.000 claims description 4
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 claims description 4
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- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical group OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 claims description 4
- ZGTMUACCHSMWAC-UHFFFAOYSA-L EDTA disodium salt (anhydrous) Chemical compound [Na+].[Na+].OC(=O)CN(CC([O-])=O)CCN(CC(O)=O)CC([O-])=O ZGTMUACCHSMWAC-UHFFFAOYSA-L 0.000 claims description 4
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- 229940099418 d- alpha-tocopherol succinate Drugs 0.000 claims description 4
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- KXGVEGMKQFWNSR-LLQZFEROSA-N deoxycholic acid Chemical compound C([C@H]1CC2)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(O)=O)C)[C@@]2(C)[C@@H](O)C1 KXGVEGMKQFWNSR-LLQZFEROSA-N 0.000 claims description 4
- KXGVEGMKQFWNSR-UHFFFAOYSA-N deoxycholic acid Natural products C1CC2CC(O)CCC2(C)C2C1C1CCC(C(CCC(O)=O)C)C1(C)C(O)C2 KXGVEGMKQFWNSR-UHFFFAOYSA-N 0.000 claims description 4
- LZCLXQDLBQLTDK-UHFFFAOYSA-N ethyl 2-hydroxypropanoate Chemical compound CCOC(=O)C(C)O LZCLXQDLBQLTDK-UHFFFAOYSA-N 0.000 claims description 4
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- WVDDGKGOMKODPV-ZQBYOMGUSA-N phenyl(114C)methanol Chemical compound O[14CH2]C1=CC=CC=C1 WVDDGKGOMKODPV-ZQBYOMGUSA-N 0.000 claims description 4
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- BHQCQFFYRZLCQQ-UHFFFAOYSA-N (3alpha,5alpha,7alpha,12alpha)-3,7,12-trihydroxy-cholan-24-oic acid Natural products OC1CC2CC(O)CCC2(C)C2C1C1CCC(C(CCC(O)=O)C)C1(C)C(O)C2 BHQCQFFYRZLCQQ-UHFFFAOYSA-N 0.000 claims description 2
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- RFVNOJDQRGSOEL-UHFFFAOYSA-N 2-hydroxyethyl octadecanoate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCCO RFVNOJDQRGSOEL-UHFFFAOYSA-N 0.000 claims description 2
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- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 claims description 2
- IELOKBJPULMYRW-NJQVLOCASA-N D-alpha-Tocopheryl Acid Succinate Chemical compound OC(=O)CCC(=O)OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C IELOKBJPULMYRW-NJQVLOCASA-N 0.000 claims description 2
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- LVGKNOAMLMIIKO-UHFFFAOYSA-N Elaidinsaeure-aethylester Natural products CCCCCCCCC=CCCCCCCCC(=O)OCC LVGKNOAMLMIIKO-UHFFFAOYSA-N 0.000 claims description 2
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- LWZFANDGMFTDAV-BURFUSLBSA-N [(2r)-2-[(2r,3r,4s)-3,4-dihydroxyoxolan-2-yl]-2-hydroxyethyl] dodecanoate Chemical compound CCCCCCCCCCCC(=O)OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O LWZFANDGMFTDAV-BURFUSLBSA-N 0.000 claims description 2
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Abstract
薬物搭載エマルジョンの製造方法を開示する。本発明は下記のステップを含んでなる：有効成分を含まない非自己乳化水中油型空エマルジョンを製造するステップ；次に、水中油型空エマルジョンへ治療的有効量の有効成分を添加し、pH値を調整して膜を通して有効成分を分配し、所望のエマルジョンを得るステップ。
【選択図】なし
A method for producing a drug-loaded emulsion is disclosed. The present invention comprises the following steps: producing a non-self-emulsifying oil-in-water empty emulsion free of active ingredients; then adding a therapeutically effective amount of the active ingredient to the oil-in-water empty emulsion, pH Adjusting the value and distributing the active ingredient through the membrane to obtain the desired emulsion.
[Selection figure] None
Description
本発明は、非自己乳化水中油型薬物搭載エマルジョンの製造方法に関する。具体的には本発明は、薬物を空のエマルジョンに添加することによる非自己乳化水中油型薬物搭載エマルジョンの製造方法に関する。 The present invention relates to a method for producing a non-self-emulsifying oil-in-water drug-loaded emulsion. Specifically, the present invention relates to a method for producing a non-self-emulsifying oil-in-water drug-loaded emulsion by adding the drug to an empty emulsion.
エマルジョンは病院で広く使用される。脂肪エマルジョンは非経口系における薬物送達担体として、薬物の安定性向上、毒性の低減、薬物放出特性の遅延化又は制御及び薬物ターゲティングの改善という利点のため４０年以上にわたり利用されてきた。近年、脂肪エマルジョンの製造方法の発展に基づき、薬物搭載エマルジョンの研究がますます関心を引くようになった。薬物搭載製品は、治療効果を有し、また患者に活力を与えることができ、患者の回復を助けるのに好ましい。 Emulsions are widely used in hospitals. Fat emulsions have been used as drug delivery carriers in parenteral systems for over 40 years due to the advantages of improved drug stability, reduced toxicity, delayed or controlled drug release characteristics, and improved drug targeting. In recent years, research on drug-loaded emulsions has attracted more and more interest based on the development of methods for producing fat emulsions. Drug-loaded products have a therapeutic effect and can energize the patient and are preferred to help the patient recover.
先行技術には、自己乳化技術を使用した薬物搭載エマルジョンの製造方法がいくつかある。例えばXiujuan Li及びLiwei Zhangは、自己乳化技術を使用して、アスピリン油中水型マイクロエマルジョンを調製した（Chemical
Research and Application, 2008年3月、20巻3号353〜355頁）。穏やかに撹拌すると、自己乳化エマルジョンは自発的に、粒子径1000 nm未満のエマルジョンを形成することができる。従って、水相又は油相を調製する際に薬物をこの系に添加することができ、エマルジョン内部相の内側に薬物を容易に封入することができる。しかしながら自己乳化エマルジョンの調製中には大量の乳化剤が必要であり、一般的には有機溶媒である共乳化剤が必然的に添加されるので、注射剤としてはより毒性の高い自己乳化エマルジョンをもたらす。
The prior art has several methods for producing drug-loaded emulsions using self-emulsifying techniques. For example, Xiujuan Li and Liwei Zhang have used a self-emulsification technique to prepare aspirin-in-water microemulsions (Chemical
Research and Application, March 2008, Vol. 20, No. 3, pages 353-355). When gently stirred, the self-emulsifying emulsion can spontaneously form an emulsion with a particle size of less than 1000 nm. Thus, the drug can be added to the system when preparing the aqueous or oil phase, and the drug can be easily encapsulated inside the emulsion internal phase. However, a large amount of an emulsifier is required during the preparation of the self-emulsifying emulsion, and generally a co-emulsifier, which is an organic solvent, is inevitably added, resulting in a more toxic self-emulsifying emulsion as an injection.
自己乳化エマルジョン中の乳化剤と共乳化剤に起因する毒性を低減するため、粒子径1000 nm未満の非自己乳化水中油型エマルジョンを調製した。この非自己乳化水中油型エマルジョンは優れた動態安定性と血管透過性を有しており、油と水との間の強い界面張力を克服するため、一般的に高速撹拌、高圧均質化又は微小流動化などにより調製した。現在のところ、非自己乳化水中油型薬物搭載エマルジョンの一般的な製造方法には、下記のステップが含まれる：すなわち、第１に、油相と水相を調製し、混合する；第２に、その粗エマルジョンを調製する；第３に、最終的なエマルジョンを得るため、上記の過酷な条件を適応して、エマルジョンの粒子径を減少させる。通常、薬物の組み込みは、第１ステップ又は第２ステップで行う。薬物組み込み方法には、下記のような方法が含まれる：（１）薬物が油溶性である場合、最初に薬物を油相中に溶解し、次に、その溶解した薬物をエマルジョンとする；（２）薬物が水溶性である場合、最初に薬物を水相中に溶解し、次に、その溶解した薬物をエマルジョンとする；（３）薬物が油相と水相の両方に不溶の場合、最初に薬物、油相又は／及び乳化剤を適切な有機溶媒中に溶解し、次に、その有機溶媒を除去して、その溶解した薬物をエマルジョンとする。 In order to reduce toxicity due to emulsifiers and coemulsifiers in self-emulsifying emulsions, non-self-emulsifying oil-in-water emulsions with a particle size of less than 1000 nm were prepared. This non-self-emulsifying oil-in-water emulsion has excellent kinetic stability and vascular permeability, and generally overcomes high interfacial tension between oil and water, so generally high speed agitation, high pressure homogenization or microscopic Prepared by fluidization and the like. At present, a typical method for producing a non-self-emulsifying oil-in-water drug-loaded emulsion includes the following steps: first, an oil phase and an aqueous phase are prepared and mixed; Prepare the crude emulsion; third, adapt the harsh conditions described above to reduce the particle size of the emulsion in order to obtain the final emulsion. Usually, the drug is incorporated in the first step or the second step. Drug incorporation methods include the following methods: (1) If the drug is oil soluble, first dissolve the drug in the oil phase and then make the dissolved drug into an emulsion; 2) If the drug is water soluble, first dissolve the drug in the aqueous phase, then make the dissolved drug into an emulsion; (3) If the drug is insoluble in both the oil and water phases, First, the drug, oil phase or / and emulsifier are dissolved in a suitable organic solvent, then the organic solvent is removed to make the dissolved drug into an emulsion.
多くの先行技術には、油相及び水相の調製の第１ステップで行う薬物の組み込みについて開示されている。これらの先行技術には、例えば中国特許出願公開第1399959A号明細書「エトミデート脂肪エマルジョン注射剤の製造方法」（特許文献１）；同第1546016A号明細書「天然ビタミンＥのナノ製剤及びその製造方法」（特許文献２）；同第1634021A号明細書「静脈内注射用新規パクリタキセルエマルジョン及びその製造方法」（特許文献３）；同第1679576A号明細書「静脈用ビンカアルカロイドの安定化水中油型エマルジョン及びその製造」（特許文献４）；同第1732936A号明細書「ニモジピンエマルジョン注射剤及びその製造方法」（特許文献５）；同第1947720A号明細書「クラリスロマイシン脂質微粒子注射剤及びその製造方法」（特許文献６）；同第1861085A号明細書「イソプロピルフェノールスフィンゴリン脂質脂肪エマルジョン及びその製造方法」（特許文献７）などがある。しかしながら中国特許出願公開第1771954A号明細書「ビノレルビン脂質微粒子注射剤及びその製造方法」（特許文献８）には、粗エマルジョン調製の第２ステップで薬物を組み込む方法が開示されている。 Many prior arts disclose drug incorporation in the first step of oil and water phase preparation. These prior arts include, for example, Chinese Patent Application Publication No. 1399959A “Method for producing etomidate fat emulsion injection” (Patent Document 1); Patent No. 1546016A “Nanoformulation of natural vitamin E and method for producing the same” No. 1634021A “Novel paclitaxel emulsion for intravenous injection and production method thereof” (Patent Literature 3); No. 1679576A “Stabilized oil-in-water emulsion of vinca alkaloid for intravenous use” No. 1732936A “Nimodipine emulsion injection and production method thereof” (Patent Literature 5); No. 1947720A “Clarithromycin lipid microparticle injection and production thereof” Method "(Patent Document 6); No. 1861085A," Isopropylphenol sphingophospholipid lipid emulsion and method for producing the same "(Patent) Document 7), and the like. However, Chinese Patent Application No. 1771954A “Vinolerubin lipid microparticle injection and method for producing the same” (Patent Document 8) discloses a method for incorporating a drug in the second step of preparing a crude emulsion.
先行技術における薬物搭載エマルジョンの一般的製造プロセスによれば、薬物が水相又は油相に可溶である場合には、薬物は通常、第１ステップ又は第２ステップで組み込まれる。すなわち、薬物は製造プロセスの初期に組み込まれ、その系に存在するが、その一方で長時間系中に留まることになり、系中において薬物と他の物質とが共に何回かの均質化を経て、最終エマルジョンが得られる。不安定な薬物では、製造プロセスにおける長い滞留時間や上記の均質化条件により引き起こされる何回かの均質化、特に強いずり応力、高温及び高圧のため、変性、不活性化、構造破壊又は分解する確率がより高まる。しかし、薬物が油相及び水相の両方に不溶である場合、通常、有機溶媒、他の共溶媒又は添加物を系に添加し、薬物の溶解性を改善しなければならない。従って、有機溶媒残留物又は製剤の複雑化が生じ、さらにはエマルジョンの安全性の問題が起こる。 According to the general manufacturing process of drug-loaded emulsions in the prior art, if the drug is soluble in the aqueous or oil phase, the drug is usually incorporated in the first step or the second step. That is, the drug is incorporated early in the manufacturing process and is present in the system, while remaining in the system for a long time, causing the drug and other substances to homogenize several times in the system. After that, the final emulsion is obtained. Unstable drugs undergo denaturation, inactivation, structural destruction or degradation due to long residence times in the manufacturing process and several homogenizations caused by the above homogenization conditions, especially strong shear stress, high temperature and pressure Probability increases. However, if the drug is insoluble in both the oil and water phases, usually organic solvents, other co-solvents or additives must be added to the system to improve the solubility of the drug. Thus, organic solvent residues or formulation complications arise, and further emulsion safety issues arise.
中国特許出願公開第1620283A号明細書（特許文献９）には、わずかに可溶又はほとんど不溶の有効成分を分散させて製造する方法が開示されている。有効成分は、市販の水中油型エマルジョンを用いて、分散系を生成するために粉砕された。この分散系は、有効成分が主に水相で見いだされるが、同時に、内部相として油滴及び有効成分結晶から成る。次に、この分散系は高圧均質化（例えば1500バールで5〜20均質化サイクル）にかけられた。均質化後、有効成分は油滴の内部相中に組み込まれ、溶解した。この薬物搭載エマルジョンの製造方法において、薬物取り込み手順は水中油型空エマルジョンを得た後にあり、系全体において薬物の滞留時間を短縮するが、一般に薬物は、水中油型空エマルジョン中に取り込まれる前に、粒子径が1000 nm未満になるまで細かく砕かれなければならない。しかしながらこの取り込みプロセスにおいては、高エネルギーの均質化が必要であり、薬物がエマルジョンの油相中に溶解する際に強力な機械エネルギーとなる。従ってこの方法は、不安定な薬物には不適当である。一方この方法では、可溶化のための有機溶媒の使用が回避されるが、多大なエネルギーを消費するエマルジョン製造装置が必要となる。 Chinese Patent Application No. 1620283A (Patent Document 9) discloses a method for producing a slightly soluble or almost insoluble active ingredient by dispersion. The active ingredient was ground using a commercially available oil-in-water emulsion to produce a dispersion. In this dispersion system, the active ingredient is found mainly in the aqueous phase, but at the same time, the internal phase consists of oil droplets and active ingredient crystals. The dispersion was then subjected to high pressure homogenization (eg, 5-20 homogenization cycles at 1500 bar). After homogenization, the active ingredient was incorporated into the internal phase of the oil droplets and dissolved. In this method for producing a drug-loaded emulsion, the drug uptake procedure is after obtaining an oil-in-water empty emulsion, reducing the residence time of the drug throughout the system, but generally before the drug is incorporated into the oil-in-water empty emulsion. In addition, it must be finely crushed until the particle size is less than 1000 nm. However, this entrapment process requires high energy homogenization and is a powerful mechanical energy as the drug dissolves in the oil phase of the emulsion. This method is therefore unsuitable for unstable drugs. On the other hand, this method avoids the use of an organic solvent for solubilization, but requires an emulsion production apparatus that consumes a great deal of energy.
Gong Mingtao及びZhang
Junshouらは、10−ヒドロキシカンプトテシン・ナノエマルジョンの調製に相転移温度法を用いた（Chinese
Journal of Natural Medicines, 2005年、3巻1号41〜43頁）（非特許文献１）。この方法では、薬物はあらかじめ調製された水中油型空エマルジョン中に取り込まれるが、温度が70℃（相転移温度）を上回る場合、薬物はエマルジョンの内部相に封入される。薬物取り込みは相転移温度以上で行われるので、熱的に不安定な薬物は制限される。
Gong Mingtao & Zhang
Junshou et al. Used the phase transition temperature method to prepare 10-hydroxycamptothecin nanoemulsions (Chinese).
Journal of Natural Medicines, 2005, Vol. 3, No. 41-43) (Non-patent Document 1). In this method, the drug is incorporated into a pre-prepared oil-in-water empty emulsion, but when the temperature exceeds 70 ° C. (phase transition temperature), the drug is encapsulated in the internal phase of the emulsion. Since drug uptake occurs above the phase transition temperature, thermally unstable drugs are limited.
薬物の不安定性及び不溶性は、薬物搭載エマルジョン調製物の品質を低下させることがある。特に当該薬物が化学的に不安定又は油相若しくは／及び水相に不溶である場合、また特に当該エマルジョンの平均粒子径が1000 nm未満である場合に品質が低下する。先行技術における薬物搭載エマルジョンの欠点を克服するため、本発明では、薬物の自動搭載技術を取り入れ、緩和な条件下で効率的に薬物を搭載する非自己乳化エマルジョン、特に粒子径が1000 nm未満の非自己乳化エマルジョンを製造した。本発明は下記のステップを含んでなる：
薬物を含まない非自己乳化水中油型空エマルジョンを製造するステップ、好ましくは、粒子径が1000 nm未満の非自己乳化水中油型空エマルジョンを製造するステップ；
空エマルジョンへ治療的有効量の薬物を添加し、pH値を調整して、好ましくは、pH値を調整して薬物の油水分配係数を増加させ、混合することにより薬物をエマルジョンの油滴中に膜を通して移行させ、薬物搭載エマルジョンを得るステップ。
Drug instability and insolubility can reduce the quality of drug-loaded emulsion preparations. Especially when the drug is chemically unstable or insoluble in the oil phase or / and aqueous phase, and especially when the average particle size of the emulsion is less than 1000 nm, the quality is reduced. In order to overcome the disadvantages of drug-loaded emulsions in the prior art, the present invention incorporates drug loading technology, and non-self-emulsifying emulsions that load drugs efficiently under mild conditions, especially those with a particle size of less than 1000 nm. A non-self-emulsifying emulsion was prepared. The present invention comprises the following steps:
Producing a non-self-emulsifying oil-in-water empty emulsion containing no drug, preferably producing a non-self-emulsifying oil-in-water empty emulsion having a particle size of less than 1000 nm;
Add therapeutically effective amount of drug to empty emulsion and adjust pH value, preferably adjust pH value to increase oil-water partition coefficient of drug and mix drug into oil droplets of emulsion Transfer through the membrane to obtain a drug-loaded emulsion.
本発明によれば、最初に、薬物を含まない非自己乳化水中油型空エマルジョンを常法により製造する。ここでのエマルジョンの粒子径は臨床的必要性を満たすべきであり、例えば1000 nm未満の粒子径である。次に、薬物を空エマルジョンに添加し、空エマルジョンの外側の水相に薬物を溶解又は分散させる。最後に、この外側相のpH値を調整し、外側相中の薬物を遊離分子型といったより脂溶性になるよう変換し、続いて、薬物の油水分配係数logPを増加させる。濃度差により、薬物は水中油型エマルジョンの外側の水相から内側の油相に自発的に移行し、その結果、薬物の自動搭載が緩和に達成される。 According to the present invention, first, a non-self-emulsifying oil-in-water empty emulsion containing no drug is produced by a conventional method. The particle size of the emulsion here should meet clinical needs, for example a particle size of less than 1000 nm. The drug is then added to the empty emulsion and the drug is dissolved or dispersed in the aqueous phase outside the empty emulsion. Finally, the pH value of this outer phase is adjusted to convert the drug in the outer phase to be more lipophilic, such as the free molecular form, and subsequently increase the oil-water partition coefficient logP of the drug. Due to the concentration difference, the drug spontaneously moves from the outer water phase to the inner oil phase of the oil-in-water emulsion, and as a result, the automatic loading of the drug is achieved in a relaxed manner.
本発明によれば、非自己乳化水中油型空エマルジョンは、治療的有効量の薬物を含まない非自己乳化水中油型エマルジョンを指している。これは先行技術によれば空の最終エマルジョンに相当する。またその粒子径は最終薬物搭載エマルジョンと等しい。このことは、本発明において薬物は、初期に油相、水相又は粗エマルジョンに添加されるということに加え、空の最終エマルジョンが製造された後に添加されることを意味する。従って、系における薬物の滞留時間が短縮される。薬物は、空の最終エマルジョンが製造された後にそのエマルジョンに添加されるので、それに続く製造プロセスは、エマルジョン粒子径を小さくするための過酷な条件を必要としない。そのため、敏感な薬物分子の構造と安定性への障害、すなわち高速撹拌や高圧下での均質化などの過酷な条件から生じる強いずり応力や高温、高圧によって引き起こされる障害を効率的に回避することができる。 According to the present invention, a non-self-emulsifying oil-in-water empty emulsion refers to a non-self-emulsifying oil-in-water emulsion that does not contain a therapeutically effective amount of the drug. This corresponds to an empty final emulsion according to the prior art. Its particle size is equal to the final drug-loaded emulsion. This means that in the present invention, in addition to being initially added to the oil phase, aqueous phase or crude emulsion, it is added after the empty final emulsion has been produced. Therefore, the residence time of the drug in the system is shortened. Since the drug is added to the emulsion after the empty final emulsion has been produced, the subsequent production process does not require harsh conditions to reduce the emulsion particle size. Therefore, efficiently avoiding obstacles to the structure and stability of sensitive drug molecules, i.e., strong shear stress, high temperature, and high pressure resulting from harsh conditions such as high-speed stirring and homogenization under high pressure. Can do.
さらに本発明によれば、薬物が空の最終エマルジョンに添加された後、その外側相のpH値を調整し、外側相の薬物を遊離分子型といったより脂溶性になるよう変換し、続いて、薬物の油水分配係数logPを増加させる。このようにして、エマルジョンの内側相と外側相の間の薬物濃度差が生じる。濃度差により、薬物は水中油型エマルジョンの外側の水相から内側の油相に自発的に移行する。これらの手順は、薬物の溶解を促進し、さらに内側相への薬物の封入を促進するために必要な機械エネルギーを低減する。一方では、薬物封入効率が改善され得る。他方では、薬物は緩和な混合方式により、水中油型エマルジョンの内側の油相中に運搬され得る。 Further in accordance with the present invention, after the drug is added to the empty final emulsion, the pH value of its outer phase is adjusted to convert the outer phase drug to be more lipophilic, such as the free molecular form, followed by Increase drug oil-water partition coefficient logP. In this way, a drug concentration difference between the inner and outer phases of the emulsion occurs. Due to the concentration difference, the drug spontaneously transfers from the outer water phase to the inner oil phase of the oil-in-water emulsion. These procedures promote the dissolution of the drug and further reduce the mechanical energy required to facilitate the encapsulation of the drug in the inner phase. On the one hand, drug encapsulation efficiency can be improved. On the other hand, the drug can be transported into the oil phase inside the oil-in-water emulsion by a gentle mixing mode.
本発明によれば、先行技術におけるいくつかの製造方法、例えば、機械的方法、代替添加法、相転移温度法、相転移法などを、非自己乳化水中油型空エマルジョンの製造に使用することができる。例として機械的方法を取り上げると、非自己乳化水中油型空エマルジョンの製造方法は下記のステップを含んでなる：（１）油相を調製する；（２）水相を調製する；（３）油相と水相とを混合し、これらを不均一に分散させた後、乳化機を使用して水中油型空エマルジョンを調製する。乳化機は、乳鉢、攪拌機、コロイド粉砕機、超音波乳化装置、高圧ホモジナイザー又は微細流動化機などである。 According to the present invention, several production methods in the prior art, such as mechanical methods, alternative addition methods, phase transition temperature methods, phase transition methods, etc. are used for the production of non-self-emulsifying oil-in-water empty emulsions. Can do. Taking the mechanical method as an example, the process for producing a non-self-emulsifying oil-in-water empty emulsion comprises the following steps: (1) preparing an oil phase; (2) preparing an aqueous phase; (3) After mixing an oil phase and an aqueous phase and dispersing them non-uniformly, an oil-in-water empty emulsion is prepared using an emulsifier. The emulsifier is a mortar, a stirrer, a colloid grinder, an ultrasonic emulsifier, a high-pressure homogenizer, a fine fluidizer, or the like.
本発明によれば、薬物は、水溶性、油溶性、又は油相及び／若しくは水相に少し可溶、わずかに可溶若しくは極めてわずかに可溶でよい。ここで少し可溶とは、1 g（又はmL）の溶質が、30〜100 mLの溶媒に溶解することを意味する；わずかに可溶とは、1 g（又はmL）の溶質が、100〜1000 mLの溶媒に溶解することを意味する；極めてわずかに可溶とは、1 g（又はmL）の溶質が、1000〜10000 mLの溶媒に溶解することを意味する。油溶性薬物は水中油型エマルジョン中に溶解した状態で存在してもよい。油溶性薬物は油滴に封入され、不均一に分散した油滴で形成されるエマルジョンを得る。水溶性薬物は、外側相のpH値を調整することにより油溶性薬物に変換することができる。その次に、当該薬物は緩和な撹拌により膜を通過することができる。そして当該薬物は油滴に封入され、不均一に分散した油滴で形成されるエマルジョンを得る。少し可溶、わずかに可溶又は極めてわずかに可溶の薬物については、これらの薬物を油相に部分的に溶解させ、かつ高度に分散したナノ結晶の形態にあるエマルジョン中に部分的に存在させ、不均一に分散した油滴と薬物結晶とが組み合わさって形成されるエマルジョンを得る。本発明によれば、薬物は、油溶性、水溶性、又は油相及び／若しくは水相に少し可溶、わずかに可溶若しくは極めてわずかに可溶のどのようなものであっても、好ましくは、pH値によって異なる溶解性を示す薬物である。 According to the present invention, the drug may be water-soluble, oil-soluble, or slightly soluble, slightly soluble or very slightly soluble in the oil and / or aqueous phase. Here slightly soluble means 1 g (or mL) of solute is dissolved in 30 to 100 mL of solvent; slightly soluble means 1 g (or mL) of solute is 100 It means to dissolve in ~ 1000 mL of solvent; very slightly soluble means 1 g (or mL) of solute is dissolved in 1000 to 10,000 mL of solvent. The oil-soluble drug may be present in a dissolved state in the oil-in-water emulsion. The oil-soluble drug is encapsulated in the oil droplets to obtain an emulsion formed with non-uniformly dispersed oil droplets. Water-soluble drugs can be converted to oil-soluble drugs by adjusting the pH value of the outer phase. The drug can then pass through the membrane with gentle agitation. The drug is then encapsulated in oil droplets to obtain an emulsion formed with non-uniformly dispersed oil droplets. For drugs that are slightly soluble, slightly soluble or very slightly soluble, these drugs are partly dissolved in the oil phase and partly present in emulsions in the form of highly dispersed nanocrystals To obtain an emulsion formed by combining nonuniformly dispersed oil droplets and drug crystals. According to the invention, the drug is preferably oil-soluble, water-soluble, or slightly soluble, slightly soluble or very slightly soluble in the oil and / or water phase. It is a drug that shows different solubility depending on pH value.
本発明によれば、薬物は、ヒト又は動物の疾患の治療のための有効成分を指し、抗腫瘍薬、心血管治療薬、抗感染薬、抗真菌薬、抗ウイルス薬、抗アレルギー薬、抗炎症薬、内分泌薬、抗精神病薬、抗菌薬、免疫抑制薬、ビタミン及び麻薬からなる群より選ばれる。特に薬物は、パクリタキセル、ドセタキセル、ビノレルビン、ビンクリスチン、ヒドロキシカンプトセシン、オキサリプラチン、リポPGE、ニモジピン、シクロスポリン、イトラコナゾール、アンホテリシン、アシクロビル、デキサメタゾン、パルミチン酸デキサメタゾン、インドメタシン、ジアゼパム、クラリスロマイシン、ピンヤンマイシン、ドキソルビシン、ビタミンＡ、ビタミンＤ２、ビタミンＥ、ビタミンＫ、ブピバカイン、プロポフォール、エトミデート、フルルビプロフェン アキセチルなどでもよい。 According to the present invention, a drug refers to an active ingredient for the treatment of human or animal diseases, such as antitumor drugs, cardiovascular drugs, anti-infective drugs, antifungal drugs, antiviral drugs, antiallergic drugs, antiallergic drugs, Selected from the group consisting of inflammatory drugs, endocrine drugs, antipsychotic drugs, antibacterial drugs, immunosuppressive drugs, vitamins and narcotics. In particular, the drugs are paclitaxel, docetaxel, vinorelbine, vincristine, hydroxycamptothecin, oxaliplatin, lipo PGE, nimodipine, cyclosporine, itraconazole, amphotericin, acyclovir, dexamethasone, dexamethasone palmitate, indomethacin, diazepam, clarithromycin, pinyanmycin , Doxorubicin, vitamin A, vitamin D 2 , vitamin E, vitamin K, bupivacaine, propofol, etomidate, flurbiprofen axetil and the like.
前記薬物は、粉末、溶液又は分散の形態で空エマルジョンに添加することができる。最初に薬物を空エマルジョンに添加する。次に外側の水相のpH値を調整し、前記エマルジョンを均一に撹拌して、最終容量になるよう水を添加する。ろ過、充填、密封及び滅菌後、本発明の製造物が得られる。 The drug can be added to the empty emulsion in the form of a powder, solution or dispersion. First, the drug is added to the empty emulsion. Next, the pH value of the outer aqueous phase is adjusted, the emulsion is stirred uniformly, and water is added to the final volume. After filtration, filling, sealing and sterilization, the product of the invention is obtained.
上記のように、本発明における混合は、エマルジョンの粒子径を減少させることには向けられていないが、濃度差のもとに薬物を内側の油相に移送する補助的な機械的方法としての役割を果たす。機械的撹拌、高速度せん断、超音波乳化、高圧均質化又は微細流動化など、好ましくは機械的撹拌及び高速度せん断という先行技術において使用される一般的な混合方法は、本発明に適用することができる。本発明の製造方法では、薬物が添加された空エマルジョン系のpH値が調整されるため、油水分配係数が改善される。濃度差を受けて薬物は自発的に内側の油相に封入され、より迅速に油相に分散する。従って本発明の混合は、高いエネルギー又はより高いエネルギー条件を必要とせず、濃度差のもとに薬物を内側の油相に移送する補助的な機械的方法としての役割を果たす。過酷な条件を伴ういくつかの混合方法、例えば超音波乳化、高圧均質化、微細流動化などであっても採用され、いくつかの条件は制御することができる。例えば、超音波周波数は下げることができ、また超音波乳化法では製造時間を短縮することができ、高圧均質化法では圧力と繰り返し時間を制御することができる。これらの方法は混合エネルギーを減少させることができ、そのため、薬物が内側の油相に入るのを促進し、その一方で薬物への悪影響を避けることができる。 As noted above, mixing in the present invention is not directed to reducing the particle size of the emulsion, but as an auxiliary mechanical method to transfer the drug to the inner oil phase under concentration differences. Play a role. General mixing methods used in the prior art, preferably mechanical stirring and high speed shearing, such as mechanical stirring, high speed shearing, ultrasonic emulsification, high pressure homogenization or microfluidization should be applied to the present invention. Can do. In the production method of the present invention, since the pH value of the empty emulsion system to which the drug is added is adjusted, the oil-water partition coefficient is improved. In response to the concentration difference, the drug is spontaneously enclosed in the inner oil phase and more rapidly disperses in the oil phase. Thus, the blends of the present invention do not require high energy or higher energy conditions and serve as an auxiliary mechanical method to transfer the drug to the inner oil phase under concentration differences. Some mixing methods with harsh conditions, such as ultrasonic emulsification, high pressure homogenization, microfluidization, etc. are also employed and some conditions can be controlled. For example, the ultrasonic frequency can be lowered, the ultrasonic emulsification method can shorten the production time, and the high pressure homogenization method can control the pressure and the repetition time. These methods can reduce the mixing energy, thus facilitating the drug entering the inner oil phase while avoiding adverse effects on the drug.
滅菌法は、先行技術におけるオートクレーブ、無菌ろ過、及び一般的なエマルジョン滅菌に使用される他の方法からなる群より選ぶことができる。 The sterilization method can be selected from the group consisting of autoclaves in the prior art, aseptic filtration, and other methods used for general emulsion sterilization.
本発明によれば、薬物搭載エマルジョンは、薬物、油溶剤、界面活性剤及び水を含んでなる。この薬物搭載エマルジョンは、薬物の異なる物理的及び化学的特性により、安定剤、可溶化剤、共溶媒、金属キレート剤、浸透圧調整剤、抗酸化剤及び防腐剤からなる群より選ばれる１種以上の成分をさらに含んでなる。 According to the present invention, the drug-loaded emulsion comprises a drug, an oil solvent, a surfactant and water. This drug-loaded emulsion is selected from the group consisting of stabilizers, solubilizers, co-solvents, metal chelators, osmotic pressure regulators, antioxidants and preservatives, depending on the different physical and chemical properties of the drug. It further comprises the above components.
本発明によれば、油溶剤は１種以上の鉱物油、植物油、動物油又は合成油を含む。前記植物油は、大豆油、ベニバナ油、トウモロコシ油、ヤシ油、ヒマシ油、ニガキモドキ油、パーム油、中鎖脂肪酸トリグリセリド、ピーナッツ油、綿実油及びこれらの混合物からなる群より選ばれる。前記動物油は、魚油、鯨油及びこれらの混合物からなる群より選ばれる。適切な油溶剤は、搭載された薬物とそのエマルジョンの投与方法に応じて選択することができる。前記油溶剤は、エマルジョン中で2〜40 w/v％の範囲にある。 According to the present invention, the oil solvent comprises one or more mineral oils, vegetable oils, animal oils or synthetic oils. The vegetable oil is selected from the group consisting of soybean oil, safflower oil, corn oil, coconut oil, castor oil, bitumen oil, palm oil, medium chain fatty acid triglyceride, peanut oil, cottonseed oil and mixtures thereof. The animal oil is selected from the group consisting of fish oil, whale oil and mixtures thereof. The appropriate oil solvent can be selected depending on the drug loaded and the method of administration of the emulsion. The oil solvent is in the range of 2-40 w / v% in the emulsion.
本発明によれば、界面活性剤はリン脂質、非イオン性界面活性剤及びこれらの混合物を含み、油相中に溶解させるか又は水相中に分散させることができる。本発明によれば、前記リン脂質は、卵レシチン、大豆レシチン、水素化卵レシチン、水素化大豆ホスファチジルコリン及び合成リン脂質からなる群より選ばれる。前記非イオン性界面活性剤は、Tween 20、Tween 40、Tween 60、Tween 80、Tween 85、Span 20、Span 40、Span 60、Span 80、ポリオキシエチレンヒマシ油、ポリ（エチレンオキシド）水素ヒマシ油、ポリ（エチレンオキシド）ステアリン酸エステル、ポロクサマー188、ポリエチレングリコールステアリン酸エステル15、ポリエチレングリコール−ビタミンＥコハク酸エステル及びこれらの混合物からなる群より選ばれる。前記界面活性剤は、エマルジョン中で0.5〜50 w/v％の範囲にある。 According to the present invention, the surfactant comprises phospholipids, nonionic surfactants and mixtures thereof and can be dissolved in the oil phase or dispersed in the aqueous phase. According to the present invention, the phospholipid is selected from the group consisting of egg lecithin, soybean lecithin, hydrogenated egg lecithin, hydrogenated soybean phosphatidylcholine and synthetic phospholipid. The nonionic surfactant is Tween 20, Tween 40, Tween 60, Tween 80, Tween 85, Span 20, Span 40, Span 60, Span 80, polyoxyethylene castor oil, poly (ethylene oxide) hydrogen castor oil, It is selected from the group consisting of poly (ethylene oxide) stearate, poloxamer 188, polyethylene glycol stearate 15, polyethylene glycol-vitamin E succinate and mixtures thereof. The surfactant is in the range of 0.5-50 w / v% in the emulsion.
本発明によれば、抗酸化剤は、水溶性抗酸化剤及び油溶性抗酸化剤からなる群より選ばれる。水溶性抗酸化剤は水相に溶解し、油溶性抗酸化剤は油相に溶解する。前記水溶性抗酸化剤は、亜硫酸ナトリウム、亜硫酸水素ナトリウム、二亜硫酸ナトリウム、アスコルビン酸、アスコルビン酸ナトリウム、Ｌ−システイン及びこれらの混合物からなる群より選ばれる。前記油溶性抗酸化剤は、α−トコフェロール、α−トコフェロール酢酸エステル、α−トコフェロールコハク酸エステル、ブチルヒドロキシアニソール（BHA）、ブチル化ヒドロキシトルエン（BHA）及びこれらの混合物からなる群より選ばれる。 According to the present invention, the antioxidant is selected from the group consisting of a water soluble antioxidant and an oil soluble antioxidant. The water-soluble antioxidant is dissolved in the water phase, and the oil-soluble antioxidant is dissolved in the oil phase. The water-soluble antioxidant is selected from the group consisting of sodium sulfite, sodium hydrogen sulfite, sodium disulfite, ascorbic acid, sodium ascorbate, L-cysteine, and mixtures thereof. The oil-soluble antioxidant is selected from the group consisting of α-tocopherol, α-tocopherol acetate, α-tocopherol succinate, butylhydroxyanisole (BHA), butylated hydroxytoluene (BHA), and mixtures thereof.
本発明によれば、金属キレート剤は、EDTA、EDTA二ナトリウム塩、EDTA二カルシウム塩及びこれらの混合物からなる群より選ばれる。 According to the present invention, the metal chelator is selected from the group consisting of EDTA, EDTA disodium salt, EDTA dicalcium salt, and mixtures thereof.
本発明によれば、浸透圧調整剤は、グリセリン、ソルビトール、マンニトール、グルコース、塩化ナトリウム及びこれらの混合物からなる群より選ばれる。 According to the invention, the osmotic pressure adjusting agent is selected from the group consisting of glycerin, sorbitol, mannitol, glucose, sodium chloride and mixtures thereof.
本発明によれば、安定剤は、オレイン酸、オレイン酸ナトリウム、コレステロール、コール酸、コール酸ナトリウム、デオキシコール酸、デオキシコール酸ナトリウム及びこれらの混合物からなる群より選ばれる。 According to the present invention, the stabilizer is selected from the group consisting of oleic acid, sodium oleate, cholesterol, cholic acid, sodium cholate, deoxycholic acid, sodium deoxycholate and mixtures thereof.
本発明によれば、防腐剤は、チョウジ油、プロピレングリコール、ソルビトール、ソルビン酸、メタン酸、ブチルパラベンカルシウム、メチルパラベンナトリウム、プロピルパラベンナトリウム、ベンジルアルコール、安息香酸及びこれらの混合物からなる群より選ばれる。 According to the present invention, the preservative is selected from the group consisting of clove oil, propylene glycol, sorbitol, sorbic acid, methanoic acid, butyl paraben calcium, methyl paraben sodium, propyl paraben sodium, benzyl alcohol, benzoic acid and mixtures thereof. .
本発明によれば、共溶媒は、オレイン酸エチル、安息香酸ベンジル、ベンジルアルコール、乳酸エチル、エタノール、１，２−プロピレングリコール、ポリエチレングリコール及びこれらの混合物からなる群より選ばれる。 According to the present invention, the co-solvent is selected from the group consisting of ethyl oleate, benzyl benzoate, benzyl alcohol, ethyl lactate, ethanol, 1,2-propylene glycol, polyethylene glycol and mixtures thereof.
本発明によれば、薬物搭載エマルジョンは、局所投与、経口投与又は非経口投与することができ、特に静脈内投与、経皮投与、皮下投与、筋肉内投与、関節内投与又は胸膜内投与することができ、好ましくは静脈内投与することができる。静脈内投与については、薬物搭載エマルジョンの平均粒子径は1000 nm未満である。 According to the present invention, the drug-loaded emulsion can be administered topically, orally or parenterally, particularly intravenously, transdermally, subcutaneously, intramuscularly, intraarticularly or intrapleurally. Preferably administered intravenously. For intravenous administration, the drug-loaded emulsion has an average particle size of less than 1000 nm.
先行技術と比較して、本発明には下記のような利点がある：
（１）本発明によれば、薬物の油水分配係数logPはpH値の調整により変化し、薬物は、空エマルジョンの油相と水相との間で再分配する。その結果、薬物は膜を通して移動し、緩和な方法により油相に分配する。従って有機溶媒は必要ではない。また、得られる製造物には残留溶媒の問題がない。
（２）薬物搭載エマルジョンの一般的な製造方法と比較して、本発明によれば、薬物は水中油型空最終エマルジョンの製造後に添加される。従って、系における薬物の滞留時間は減少する。さらに、高圧又は高エネルギーの機械的撹拌又は均質化は、薬物添加手順中又はその後に行われるので、製造過程における薬物の分解を低減又は回避することができる。
（３）本発明によれば、製造方法は簡便であり、高エネルギーを生み出す乳化装置のような特別なエマルジョン製造装置は必要ではない。本発明の製造方法は、製剤の大量工業生産に有利である。
Compared to the prior art, the present invention has the following advantages:
(1) According to the present invention, the oil-water partition coefficient logP of the drug is changed by adjusting the pH value, and the drug is redistributed between the oil phase and the water phase of the empty emulsion. As a result, the drug moves through the membrane and distributes to the oil phase in a relaxed manner. Thus, no organic solvent is necessary. Further, the obtained product has no problem of residual solvent.
(2) Compared with the general method for producing a drug-loaded emulsion, according to the present invention, the drug is added after the production of the oil-in-water empty final emulsion. Therefore, the residence time of the drug in the system is reduced. In addition, high pressure or high energy mechanical agitation or homogenization occurs during or after the drug addition procedure, thereby reducing or avoiding drug degradation during the manufacturing process.
(3) According to the present invention, the production method is simple, and no special emulsion production apparatus such as an emulsification apparatus that produces high energy is required. The production method of the present invention is advantageous for mass production of pharmaceutical preparations.
下記の実施例は本発明を説明しようとするものであり、本発明の範囲をなんら限定しようとするものではない。 The following examples are intended to illustrate the invention and are not intended to limit the scope of the invention in any way.
酒石酸ビノレルビン 0.05％
大豆油 5％
卵レシチン 2％
注射用水 1000 mLになるまで
不活性ガスによる保護下、50 gの大豆油を取り、75℃に予熱した；また20 gの卵レシチンを適量の注射用水に添加した後、この液を均一に撹拌し水相を得た。この水相は75℃に予熱した。高速撹拌下、当該水相を前記油相に添加し、この液を高圧ホモジナイザーにより均一にホモジナイズして、粒子径1000 nm未満の水中油型空エマルジョンを得た。このエマルジョンに0.5 gの酒石酸ビノレルビンを添加し、pH値を8.0に調整して機械的に撹拌した後、定容積の1000 mLまで注射用水を添加した。エマルジョンは0.22 μmフィルターでろ過滅菌した後、窒素の保護下で充填し、容器を密封した。
Vinorelbine tartrate 0.05%
Soybean oil 5%
Egg lecithin 2%
Water for injection up to 1000 mL
Under protection by inert gas, 50 g of soybean oil was taken and preheated to 75 ° C .; 20 g of egg lecithin was added to an appropriate amount of water for injection, and the solution was stirred uniformly to obtain an aqueous phase. This aqueous phase was preheated to 75 ° C. Under high-speed stirring, the aqueous phase was added to the oil phase, and this liquid was homogenized with a high-pressure homogenizer to obtain an oil-in-water empty emulsion having a particle size of less than 1000 nm. To this emulsion, 0.5 g of vinorelbine tartrate was added, the pH value was adjusted to 8.0 and mechanically stirred, and then water for injection was added to a constant volume of 1000 mL. The emulsion was sterilized by filtration through a 0.22 μm filter, then filled under nitrogen protection, and the container was sealed.
塩酸ブピバカイン 0.1％
ヒマシ油 10％
大豆レシチン 2％
無水亜硫酸ナトリウム 0.2％
グリセリン 2.5％
注射用水 1000 mLになるまで
不活性ガスによる保護下、100 gのヒマシ油を取り、60℃に予熱した；また20 gの大豆レシチン、2 gの無水亜硫酸ナトリウム及び25 gのグリセリンを適量の注射用水に添加した後、この液を均一に撹拌し水相を得た。この水相は60℃に予熱した。高速撹拌下、油相と水相とを均一に混合し、高圧ホモジナイザーによりホモジナイズして、粒子径1000 nm未満の水中油型空エマルジョンを得た。このエマルジョンに1 gの塩酸ブピバカインを添加し、pH値を7.0に調整して機械的に撹拌した後、定容積の1000 mLまで注射用水を添加した。エマルジョンは0.22 μmフィルターでろ過滅菌した後、窒素の保護下で充填し、容器を密封した。
Bupivacaine hydrochloride 0.1%
Castor oil 10%
Soy lecithin 2%
Anhydrous sodium sulfite 0.2%
Glycerin 2.5%
Water for injection up to 1000 mL
Under protection by inert gas, 100 g castor oil was taken and preheated to 60 ° C; 20 g soy lecithin, 2 g anhydrous sodium sulfite and 25 g glycerin were added to the appropriate amount of water for injection and The liquid was stirred uniformly to obtain an aqueous phase. This aqueous phase was preheated to 60 ° C. Under high-speed stirring, the oil phase and the aqueous phase were uniformly mixed, and homogenized with a high-pressure homogenizer to obtain an oil-in-water type empty emulsion having a particle diameter of less than 1000 nm. 1 g of bupivacaine hydrochloride was added to the emulsion, the pH value was adjusted to 7.0 and mechanically stirred, and then water for injection was added to a constant volume of 1000 mL. The emulsion was sterilized by filtration through a 0.22 μm filter, then filled under nitrogen protection, and the container was sealed.
工程中pH値が4.0に調整されたことを除き、ここでの製剤は実施例２と同一である。 The formulation here is the same as Example 2, except that the pH value was adjusted to 4.0 during the process.
工程中pH値が5.0に調整されたことを除き、ここでの製剤は実施例２と同一である。 The formulation here is the same as in Example 2, except that the pH value was adjusted to 5.0 during the process.
工程中pH値が6.0に調整されたことを除き、ここでの製剤は実施例２と同一である。 The formulation here is the same as in Example 2, except that the pH value was adjusted to 6.0 during the process.
工程中pH値が8.0に調整されたことを除き、ここでの製剤は実施例２と同一である。 The formulation here is the same as Example 2 except that the pH value was adjusted to 8.0 during the process.
実施例２〜６の含有量、類縁物質、封入効率及び粒子径を測定し、その結果を図１及び２に示した：
実施例２〜６より、エマルジョンのpH値は、塩酸ブピバカインの油水分配係数を変化させることによって封入効率に明らかに影響することが示される。pH値が低くなるほど薬物の油水分配係数は低くなる。pH値が低いと、エマルジョンの内側相に入る薬物の量が少なくなり、また封入効率が低くなる。pH値が上がるに従い、封入効率は明らかに増加する。 Examples 2-6 show that the pH value of the emulsion clearly affects the encapsulation efficiency by changing the oil-water partition coefficient of bupivacaine hydrochloride. The lower the pH value, the lower the oil-water partition coefficient of the drug. A low pH value results in less drug entering the inner phase of the emulsion and lower encapsulation efficiency. As the pH value increases, the encapsulation efficiency clearly increases.
製剤が異なると、１ヵ月間の加速試験後の平均粒子径、含有量及び類縁物質の変化は異なった。この考えられる理由は、pH値が低い場合、塩酸ブピバカインは水溶性塩酸塩の形態にあったということである。pH値が低いと油水分配係数も低く、脂溶性遊離塩基の形態にある薬物より安定である。また類縁物質は、pH値が高い製剤より少ない。pH値は、含有量及び粒子径には有意な影響を及ぼさなかった。 Different formulations differed in changes in average particle size, content and related substances after a one month accelerated test. The possible reason for this is that when the pH value was low, bupivacaine hydrochloride was in the form of water-soluble hydrochloride. Lower pH values result in lower oil-water partition coefficients and are more stable than drugs in the form of fat-soluble free bases. Also, there are fewer related substances than formulations with high pH values. The pH value had no significant effect on content and particle size.
塩酸イリノテカン 0.05％
大豆油 10％
卵レシチン 2％
ポロクサマー 2％
グリセリン 2.5％
注射用水 1000 mLになるまで
不活性ガスによる保護下、100 gの大豆油を油相として取った；また20 gの卵レシチン、20 gのポロクサマー及び25 gのグリセリンを適量の注射用水に添加した後、この液を均一に撹拌し水相を得た。高速撹拌下、油相と水相とを均一に混合し、高圧ホモジナイザーによりホモジナイズして、粒子径1000 nm未満の水中油型空エマルジョンを得た。このエマルジョンに0.5 gの塩酸イリノテカンを添加し、pH値を8.0に調整して、微小ジェット流ホモジナイザーで乳化した後、定容積の1000 mLまで注射用水を添加した。エマルジョンは0.22 μmフィルターでろ過滅菌した後、窒素の保護下で充填し、容器を密封した。
Irinotecan hydrochloride 0.05%
Soybean oil 10%
Egg lecithin 2%
Polox Summer 2%
Glycerin 2.5%
Water for injection up to 1000 mL
Under protection by inert gas, 100 g of soybean oil was taken as the oil phase; and after addition of 20 g egg lecithin, 20 g poloxamer and 25 g glycerin to the appropriate amount of water for injection, the solution was homogeneously mixed. Stir to obtain an aqueous phase. Under high-speed stirring, the oil phase and the aqueous phase were uniformly mixed, and homogenized with a high-pressure homogenizer to obtain an oil-in-water type empty emulsion having a particle diameter of less than 1000 nm. To this emulsion, 0.5 g of irinotecan hydrochloride was added, the pH value was adjusted to 8.0, emulsified with a fine jet flow homogenizer, and water for injection was added to a constant volume of 1000 mL. The emulsion was sterilized by filtration through a 0.22 μm filter, then filled under nitrogen protection, and the container was sealed.
ビノレルビン 0.2％
大豆油 5％
卵レシチン 2％
注射用水 1000 mLになるまで
不活性ガスによる保護下、50 gの大豆油を取り、75℃に予熱した；また20 gの卵レシチンを適量の注射用水に添加した後、この液を均一に撹拌し水相を得た。この水相は75℃に予熱した。高速撹拌下、当該水相を前記油相に添加し、この液を高圧ホモジナイザーにより均一にホモジナイズして、粒子径1000 nm未満の水中油型空エマルジョンを得た。このエマルジョンに2 gのビノレルビンを添加し、pH値を8.0に調整して機械的に撹拌した後、定容積の1000 mLまで注射用水を添加した。エマルジョンは0.22 μmフィルターでろ過滅菌した後、窒素の保護下で充填し、容器を密封した。
Vinorelbine 0.2%
Soybean oil 5%
Egg lecithin 2%
Water for injection up to 1000 mL
Under protection by inert gas, 50 g of soybean oil was taken and preheated to 75 ° C .; 20 g of egg lecithin was added to an appropriate amount of water for injection, and the solution was stirred uniformly to obtain an aqueous phase. This aqueous phase was preheated to 75 ° C. Under high-speed stirring, the aqueous phase was added to the oil phase, and this liquid was homogenized with a high-pressure homogenizer to obtain an oil-in-water empty emulsion having a particle size of less than 1000 nm. To this emulsion, 2 g of vinorelbine was added, the pH value was adjusted to 8.0 and mechanically stirred, and then water for injection was added to a constant volume of 1000 mL. The emulsion was sterilized by filtration through a 0.22 μm filter, then filled under nitrogen protection, and the container was sealed.
ドセタキセル 0.05％
中鎖脂肪酸トリグリセリド 15％
卵レシチン 2％
Tween 80 0.5％
オレイン酸 0.4％
グリセリン 2.5％
α−トコフェロール 0.05％
注射用水 1000 mLになるまで
不活性ガスによる保護下、150 gの中鎖脂肪酸トリグリセリド、4 gのオレイン酸、0.5 gのα−トコフェロール及び5 gのTween 80を均一に撹拌し油相を得た。この油相は70℃に予熱した；20 gの卵レシチン及び25 gのグリセリンを適量の注射用水に添加した後、この液を均一に撹拌し水相を得た。この水相は70℃に予熱した。高速撹拌下、油相と水相とを均一に混合し、高圧ホモジナイザーによりホモジナイズして、粒子径1000 nm未満の水中油型空エマルジョンを得た。このエマルジョンに0.5 gのドセタキセルを添加し、pH値を5.0に調整して、微小ジェット流ホモジナイザーで乳化した後、定容積の1000 mLまで注射用水を添加した。エマルジョンは0.22 μmフィルターでろ過滅菌した後、窒素の保護下で充填し、容器を密封した。
Docetaxel 0.05%
Medium chain fatty acid triglycerides 15%
Egg lecithin 2%
Tween 80 0.5%
Oleic acid 0.4%
Glycerin 2.5%
α-Tocopherol 0.05%
Water for injection up to 1000 mL
Under protection with an inert gas, 150 g of medium chain fatty acid triglyceride, 4 g of oleic acid, 0.5 g of α-tocopherol and 5 g of Tween 80 were uniformly stirred to obtain an oil phase. This oil phase was preheated to 70 ° C .; 20 g egg lecithin and 25 g glycerin were added to an appropriate amount of water for injection, and then the solution was stirred uniformly to obtain an aqueous phase. This aqueous phase was preheated to 70 ° C. Under high-speed stirring, the oil phase and the aqueous phase were uniformly mixed, and homogenized with a high-pressure homogenizer to obtain an oil-in-water type empty emulsion having a particle diameter of less than 1000 nm. 0.5 g of docetaxel was added to this emulsion, the pH value was adjusted to 5.0, and after emulsification with a fine jet flow homogenizer, water for injection was added to a constant volume of 1000 mL. The emulsion was sterilized by filtration through a 0.22 μm filter, then filled under nitrogen protection, and the container was sealed.
アンホテリシンＢ 0.2％
魚油 10％
卵レシチン 2％
オレイン酸ナトリウム 0.1％
グリセリン 2.5％
EDTA二ナトリウム塩 0.01％
注射用水 1000 mLになるまで
不活性ガスによる保護下、100 gの魚油を取り、70℃に予熱した；また20 gの卵レシチン、1 gのオレイン酸ナトリウム、0.1 gのEDTA二ナトリウム塩及び25 gのグリセリンを適量の注射用水に添加した後、この液を均一に撹拌し水相を得た。この水相は70℃に予熱した。高速撹拌下、油相と水相とを均一に混合し、高圧ホモジナイザーによりホモジナイズして、水中油型空エマルジョンを得た。このエマルジョンに2 gのアンホテリシンＢを添加し、pH値を7.0に調整して、粒子径が1000 nm未満になるまで高圧ホモジナイザーで乳化した後、定容積の1000 mLまで注射用水を添加した。エマルジョンは0.22 μmフィルターでろ過滅菌した後、窒素の保護下で充填し、容器を密封した。
Amphotericin B 0.2%
10% fish oil
Egg lecithin 2%
Sodium oleate 0.1%
Glycerin 2.5%
EDTA disodium salt 0.01%
Water for injection up to 1000 mL
Under protection with inert gas, 100 g of fish oil was taken and preheated to 70 ° C; 20 g egg lecithin, 1 g sodium oleate, 0.1 g EDTA disodium salt and 25 g glycerin After adding to water, this liquid was stirred uniformly to obtain an aqueous phase. This aqueous phase was preheated to 70 ° C. Under high-speed stirring, the oil phase and the aqueous phase were uniformly mixed, and homogenized with a high-pressure homogenizer to obtain an oil-in-water empty emulsion. 2 g of amphotericin B was added to the emulsion, the pH value was adjusted to 7.0, and the mixture was emulsified with a high-pressure homogenizer until the particle size was less than 1000 nm, and then water for injection was added to a constant volume of 1000 mL. The emulsion was sterilized by filtration through a 0.22 μm filter, then filled under nitrogen protection, and the container was sealed.
リポPGE 0.001％
大豆油 10％
卵レシチン 1.2％
オレイン酸 0.1％
グリセリン 2.5％
注射用水 1000 mLになるまで
不活性ガスによる保護下、100 gの大豆油及び1 gのオレイン酸を均一に撹拌し油相を得た；12 gの卵レシチン及び25 gのグリセリンを適量の注射用水に添加した後、この液を均一に撹拌し水相を得た。高速撹拌下、油相と水相とを均一に混合し、高圧ホモジナイザーによりホモジナイズして、粒子径1000 nm未満の水中油型空エマルジョンを得た。このエマルジョンに10 mgのリポPGEを添加し、pH値を5.0に調整して、高圧ホモジナイザーで乳化した後、定容積の1000 mLまで注射用水を添加した。エマルジョンは0.22 μmフィルターでろ過滅菌した後、窒素の保護下で充填し、容器を密封した。
Lipo PGE 0.001%
Soybean oil 10%
Egg lecithin 1.2%
Oleic acid 0.1%
Glycerin 2.5%
Water for injection up to 1000 mL
Under protection with inert gas, 100 g soybean oil and 1 g oleic acid were uniformly stirred to obtain an oil phase; 12 g egg lecithin and 25 g glycerin were added to an appropriate amount of water for injection and The liquid was stirred uniformly to obtain an aqueous phase. Under high-speed stirring, the oil phase and the aqueous phase were uniformly mixed, and homogenized with a high-pressure homogenizer to obtain an oil-in-water type empty emulsion having a particle diameter of less than 1000 nm. 10 mg of lipo-PGE was added to this emulsion, the pH value was adjusted to 5.0, and after emulsification with a high-pressure homogenizer, water for injection was added to a constant volume of 1000 mL. The emulsion was sterilized by filtration through a 0.22 μm filter, then filled under nitrogen protection, and the container was sealed.
ジアゼパム 0.1％
大豆油 10％
卵レシチン 1.2％
オレイン酸ナトリウム 0.05％
グリセリン 2.5％
注射用水 1000 mLになるまで
不活性ガスによる保護下、100 gの大豆油を油相として取った；また12 gの卵レシチン、0.5 gのオレイン酸ナトリウム及び25 gのグリセリンを適量の注射用水に添加した後、この液を均一に撹拌し水相を得た。高速撹拌下、油相と水相とを均一に混合し、高圧ホモジナイザーによりホモジナイズして、粒子径1000 nm未満の水中油型空エマルジョンを得た。このエマルジョンに1 gのジアゼパムを添加し、pH値を8.0に調整して、高圧ホモジナイザーで乳化した後、定容積の1000 mLまで注射用水を添加した。エマルジョンは0.22 μmフィルターでろ過滅菌した後、窒素の保護下で充填し、容器を密封した。
Diazepam 0.1%
Soybean oil 10%
Egg lecithin 1.2%
Sodium oleate 0.05%
Glycerin 2.5%
Water for injection up to 1000 mL
Under protection by inert gas, 100 g of soybean oil was taken as the oil phase; after addition of 12 g egg lecithin, 0.5 g sodium oleate and 25 g glycerin to the appropriate amount of water for injection, The mixture was stirred uniformly to obtain an aqueous phase. Under high-speed stirring, the oil phase and the aqueous phase were uniformly mixed, and homogenized with a high-pressure homogenizer to obtain an oil-in-water type empty emulsion having a particle diameter of less than 1000 nm. 1 g of diazepam was added to this emulsion, the pH value was adjusted to 8.0, and the mixture was emulsified with a high-pressure homogenizer, and then water for injection was added to a constant volume of 1000 mL. The emulsion was sterilized by filtration through a 0.22 μm filter, then filled under nitrogen protection, and the container was sealed.
エトミデート 0.1％
大豆油 10％
卵レシチン 1.2％
グリセリン 2.5％
注射用水 1000 mLになるまで
不活性ガスによる保護下、100 gの大豆油を取り、50℃に予熱した；また12 gの卵レシチン及び25 gのグリセリンを適量の注射用水に添加した後、この液を均一に撹拌し水相を得た。この水相は50℃に予熱した。高速撹拌下、油相と水相とを均一に混合し、高圧ホモジナイザーによりホモジナイズして、粒子径1000 nm未満の水中油型空エマルジョンを得た。このエマルジョンに1 gのエトミデートを添加し、pH値を5.0に調整して、高圧ホモジナイザーで乳化した後、定容積の1000 mLまで注射用水を添加した。エマルジョンは0.22 μmフィルターでろ過滅菌した後、窒素の保護下で充填し、容器を密封した。
Etomi Date 0.1%
Soybean oil 10%
Egg lecithin 1.2%
Glycerin 2.5%
Water for injection up to 1000 mL
Under protection by inert gas, take 100 g of soybean oil and preheat to 50 ° C; add 12 g egg lecithin and 25 g glycerin to the appropriate amount of water for injection; Got the phase. This aqueous phase was preheated to 50 ° C. Under high-speed stirring, the oil phase and the aqueous phase were uniformly mixed, and homogenized with a high-pressure homogenizer to obtain an oil-in-water type empty emulsion having a particle diameter of less than 1000 nm. 1 g of etomidate was added to this emulsion, the pH value was adjusted to 5.0, emulsified with a high-pressure homogenizer, and water for injection was added to a constant volume of 1000 mL. The emulsion was sterilized by filtration through a 0.22 μm filter, then filled under nitrogen protection, and the container was sealed.
プロポフォール 0.1％
大豆油 5％
中鎖脂肪酸トリグリセリド 5％
卵レシチン 1.2％
グリセリン 2.5％
注射用水 1000 mLになるまで
不活性ガスによる保護下、50 gの大豆油及び50 gの中鎖脂肪酸トリグリセリドを均一に撹拌し油相を得た。この油相は60℃に予熱した；12 gの卵レシチン及び25 gのグリセリンを適量の注射用水に添加した後、この液を均一に撹拌し水相を得た。この水相は60℃に予熱した。高速撹拌下、油相と水相とを均一に混合し、高圧ホモジナイザーによりホモジナイズして、粒子径1000 nm未満の水中油型空エマルジョンを得た。このエマルジョンに1 gのプロポフォールを添加し、pH値を8.0に調整して、高圧ホモジナイザーで乳化した後、定容積の1000 mLまで注射用水を添加した。エマルジョンは0.22 μmフィルターでろ過滅菌した後、窒素の保護下で充填し、容器を密封した。
Propofol 0.1%
Soybean oil 5%
Medium chain triglyceride 5%
Egg lecithin 1.2%
Glycerin 2.5%
Water for injection up to 1000 mL
Under protection with an inert gas, 50 g of soybean oil and 50 g of medium-chain fatty acid triglyceride were uniformly stirred to obtain an oil phase. The oil phase was preheated to 60 ° C .; 12 g egg lecithin and 25 g glycerin were added to an appropriate amount of water for injection, and the liquid was stirred uniformly to obtain an aqueous phase. This aqueous phase was preheated to 60 ° C. Under high-speed stirring, the oil phase and the aqueous phase were uniformly mixed, and homogenized with a high-pressure homogenizer to obtain an oil-in-water type empty emulsion having a particle diameter of less than 1000 nm. 1 g of propofol was added to this emulsion, the pH value was adjusted to 8.0, emulsified with a high-pressure homogenizer, and water for injection was added to a constant volume of 1000 mL. The emulsion was sterilized by filtration through a 0.22 μm filter, then filled under nitrogen protection, and the container was sealed.
シクロスポリン 0.1％
中鎖脂肪酸トリグリセリド 3％
ポリオキシエチレンヒマシ油 10％
PEG-400 5％
NaCl 0.4％
注射用水 1000 mLになるまで
不活性ガスによる保護下、30 gの中鎖脂肪酸トリグリセリドを取り、60℃に予熱した；100 gのポリオキシエチレンヒマシ油、50 gのPEG-400及び4 gのNaClを適量の注射用水に添加した後、この液を均一に撹拌し水相を得た。この水相は60℃に予熱した。高速撹拌下、油相と水相とを均一に混合し、高圧ホモジナイザーによりホモジナイズして、粒子径1000 nm未満の水中油型空エマルジョンを得た。このエマルジョンに1 gのシクロスポリンを添加し、pH値を7.4に調整して、高速度せん断で乳化した後、定容積の1000 mLまで注射用水を添加した。エマルジョンは0.22 μmフィルターでろ過滅菌した後、窒素の保護下で充填し、容器を密封した。
Cyclosporine 0.1%
Medium chain triglyceride 3%
Polyoxyethylene castor oil 10%
PEG-400 5%
NaCl 0.4%
Water for injection up to 1000 mL
Under protection by inert gas, take 30 g of medium chain fatty acid triglycerides and preheat to 60 ° C; add 100 g polyoxyethylene castor oil, 50 g PEG-400 and 4 g NaCl to appropriate amount of water for injection After that, this liquid was uniformly stirred to obtain an aqueous phase. This aqueous phase was preheated to 60 ° C. Under high-speed stirring, the oil phase and the aqueous phase were uniformly mixed, and homogenized with a high-pressure homogenizer to obtain an oil-in-water type empty emulsion having a particle diameter of less than 1000 nm. 1 g of cyclosporine was added to this emulsion, the pH value was adjusted to 7.4, emulsification was carried out by high-speed shearing, and water for injection was added to a constant volume of 1000 mL. The emulsion was sterilized by filtration through a 0.22 μm filter, then filled under nitrogen protection, and the container was sealed.
ニモジピン 0.1％
大豆油 15％
大豆レシチン 1.2％
オレイン酸ナトリウム 0.05％
グリセリン 2.25％
注射用水 1000 mLになるまで
不活性ガスによる保護下、150 gの大豆油及び12 gの大豆レシチンを均一に撹拌し油相を得た。この油相は60℃に予熱した；22.5 gのグリセリン及び0.5 gのオレイン酸ナトリウムを適量の注射用水に添加した後、この液を均一に撹拌し水相を得た。この水相は60℃に予熱した。高速撹拌下、油相と水相とを均一に混合し、高圧ホモジナイザーによりホモジナイズして、粒子径1000 nm未満の水中油型空エマルジョンを得た。このエマルジョンに1 gのニモジピンを添加し、pH値を8.0に調整して、高圧ホモジナイザーで乳化した後、定容積の1000 mLまで注射用水を添加した。エマルジョンは0.22 μmフィルターでろ過滅菌した後、窒素の保護下で充填し、容器を密封した。
Nimodipine 0.1%
Soybean oil 15%
Soy lecithin 1.2%
Sodium oleate 0.05%
Glycerin 2.25%
Water for injection up to 1000 mL
Under protection by inert gas, 150 g of soybean oil and 12 g of soybean lecithin were uniformly stirred to obtain an oil phase. The oil phase was preheated to 60 ° C .; 22.5 g of glycerin and 0.5 g of sodium oleate were added to an appropriate amount of water for injection, and the solution was stirred uniformly to obtain an aqueous phase. This aqueous phase was preheated to 60 ° C. Under high-speed stirring, the oil phase and the aqueous phase were uniformly mixed, and homogenized with a high-pressure homogenizer to obtain an oil-in-water type empty emulsion having a particle diameter of less than 1000 nm. To this emulsion, 1 g of nimodipine was added, the pH value was adjusted to 8.0, and emulsified with a high-pressure homogenizer, and then water for injection was added to a constant volume of 1000 mL. The emulsion was sterilized by filtration through a 0.22 μm filter, then filled under nitrogen protection, and the container was sealed.
ビタミンＤ２ 0.5％
大豆油 5％
大豆レシチン 1.5％
グリセリン 2.25％
注射用水 1000 mLになるまで
不活性ガスによる保護下、50 gの大豆油及び15 gの大豆レシチンを均一に撹拌し油相を得た。この油相は70℃に予熱した；22.5 gのグリセリンを適量の注射用水に添加した後、この液を均一に撹拌し水相を得た。この水相は70℃に予熱した。高速撹拌下、油相と水相とを均一に混合し、高圧ホモジナイザーによりホモジナイズして、粒子径1000 nm未満の水中油型空エマルジョンを得た。このエマルジョンに5 gのビタミンＤ２を添加し、pH値を8.0に調整して、高圧ホモジナイザーで乳化した後、定容積の1000 mLまで注射用水を添加した。エマルジョンは0.22 μmフィルターでろ過滅菌した後、窒素の保護下で充填し、容器を密封した。
Vitamin D 2 0.5%
Soybean oil 5%
Soy lecithin 1.5%
Glycerin 2.25%
Water for injection up to 1000 mL
Under protection with an inert gas, 50 g of soybean oil and 15 g of soybean lecithin were uniformly stirred to obtain an oil phase. This oil phase was preheated to 70 ° C .; 22.5 g of glycerin was added to an appropriate amount of water for injection, and then the liquid was stirred uniformly to obtain an aqueous phase. This aqueous phase was preheated to 70 ° C. Under high-speed stirring, the oil phase and the aqueous phase were uniformly mixed, and homogenized with a high-pressure homogenizer to obtain an oil-in-water type empty emulsion having a particle diameter of less than 1000 nm. The emulsion was added Vitamin D 2 of 5 g, to adjust the pH value to 8.0, were emulsified by a high pressure homogenizer, was added water for injection to 1000 mL of a constant volume. The emulsion was sterilized by filtration through a 0.22 μm filter, then filled under nitrogen protection, and the container was sealed.
アシクロビル 0.5％
大豆油 10％
大豆レシチン 2％
オレイン酸ナトリウム 0.05％
グリセリン 2.25％
注射用水 1000 mLになるまで
不活性ガスによる保護下、100 gの大豆油を取り、70℃に予熱した；20 gの大豆レシチン、22.5 gのグリセリン及び0.5 gのオレイン酸ナトリウムを適量の注射用水に添加した後、この液を均一に撹拌し水相を得た。この水相は70℃に予熱した。高速撹拌下、油相と水相とを均一に混合し、高圧ホモジナイザーによりホモジナイズして、粒子径1000 nm未満の水中油型空エマルジョンを得た。このエマルジョンに5 gのアシクロビルを添加し、pH値を8.0に調整して、高圧ホモジナイザーで乳化した後、定容積の1000 mLまで注射用水を添加した。エマルジョンは0.22 μmフィルターでろ過滅菌した後、窒素の保護下で充填し、容器を密封した。
Acyclovir 0.5%
Soybean oil 10%
Soy lecithin 2%
Sodium oleate 0.05%
Glycerin 2.25%
Water for injection up to 1000 mL
Under protection by inert gas, 100 g of soybean oil was taken and preheated to 70 ° C; 20 g soy lecithin, 22.5 g glycerin and 0.5 g sodium oleate were added to the appropriate amount of water for injection and Were uniformly stirred to obtain an aqueous phase. This aqueous phase was preheated to 70 ° C. Under high-speed stirring, the oil phase and the aqueous phase were uniformly mixed, and homogenized with a high-pressure homogenizer to obtain an oil-in-water type empty emulsion having a particle diameter of less than 1000 nm. 5 g of acyclovir was added to this emulsion, the pH value was adjusted to 8.0, and emulsified with a high-pressure homogenizer, and then water for injection was added to a constant volume of 1000 mL. The emulsion was sterilized by filtration through a 0.22 μm filter, then filled under nitrogen protection, and the container was sealed.
薬物がクラリスロマイシンに置き換わり、製剤中の濃度が0.1％であることを除き、ここでの製剤は実施例１８と同一である。 The formulation here is identical to Example 18 except that the drug is replaced by clarithromycin and the concentration in the formulation is 0.1%.
薬物がデキサメタゾンに置き換わり、製剤中の濃度が0.1％であることを除き、ここでの製剤は実施例１８と同一である。 The formulation here is identical to Example 18 except that the drug is replaced by dexamethasone and the concentration in the formulation is 0.1%.
薬物がドキソルビシンに置き換わり、製剤中の濃度が0.1％であることを除き、ここでの製剤は実施例１８と同一である。
The formulation here is identical to Example 18 except that the drug is replaced by doxorubicin and the concentration in the formulation is 0.1%.
Claims (19)
薬物を含まない非自己乳化水中油型空エマルジョンを製造するステップ、好ましくは、粒子径が1000 nm未満の非自己乳化水中油型空エマルジョンを製造するステップ；
空エマルジョンへ治療的有効量の薬物を添加し、pH値を調整して、好ましくは、pH値を調整して薬物の油水分配係数を増加させ、混合することにより薬物をエマルジョンの油滴中に膜を通して移行させ、薬物搭載エマルジョンを得るステップ。 A method for producing a non-self-emulsifying oil-in-water drug-loaded emulsion comprising the following steps:
Producing a non-self-emulsifying oil-in-water empty emulsion containing no drug, preferably producing a non-self-emulsifying oil-in-water empty emulsion having a particle size of less than 1000 nm;
Add therapeutically effective amount of drug to empty emulsion and adjust pH value, preferably adjust pH value to increase oil-water partition coefficient of drug and mix drug into oil droplets of emulsion Transfer through the membrane to obtain a drug-loaded emulsion.
19. The method of claim 18, wherein when the drug-loaded emulsion is administered intravenously, the average particle size of the oil droplets in the emulsion is less than 1000 nm.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2009100525352A CN101904814A (en) | 2009-06-04 | 2009-06-04 | Preparation method of drug loaded emulsion |
| CN200910052535.2 | 2009-06-04 | ||
| PCT/CN2010/073500 WO2010139278A1 (en) | 2009-06-04 | 2010-06-03 | Preparation method of drug loaded emulsion |
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| JP2012528804A true JP2012528804A (en) | 2012-11-15 |
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| JP2012513464A Withdrawn JP2012528804A (en) | 2009-06-04 | 2010-06-03 | Method for producing drug-loaded emulsion |
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|---|---|
| US (1) | US20120177699A1 (en) |
| EP (1) | EP2438909A1 (en) |
| JP (1) | JP2012528804A (en) |
| KR (1) | KR20120027298A (en) |
| CN (2) | CN101904814A (en) |
| AU (1) | AU2010256130A1 (en) |
| BR (1) | BRPI1010950A2 (en) |
| CA (1) | CA2762918A1 (en) |
| HK (1) | HK1154502A1 (en) |
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| WO2018164121A1 (en) * | 2017-03-06 | 2018-09-13 | 丸石製薬株式会社 | Acidic emulsion composition containing local anesthetic agent |
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-
2009
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- 2010-06-03 EP EP10782982A patent/EP2438909A1/en not_active Withdrawn
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- 2010-06-03 WO PCT/CN2010/073500 patent/WO2010139278A1/en active Application Filing
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2013538843A (en) * | 2010-10-01 | 2013-10-17 | ニューロバイブ ファーマシューティカル アクチエボラグ | Cyclosporine emulsion |
| WO2018164121A1 (en) * | 2017-03-06 | 2018-09-13 | 丸石製薬株式会社 | Acidic emulsion composition containing local anesthetic agent |
Also Published As
| Publication number | Publication date |
|---|---|
| WO2010139278A1 (en) | 2010-12-09 |
| KR20120027298A (en) | 2012-03-21 |
| HK1154502A1 (en) | 2012-04-27 |
| AU2010256130A1 (en) | 2012-01-19 |
| CN102159188B (en) | 2014-07-09 |
| EP2438909A1 (en) | 2012-04-11 |
| US20120177699A1 (en) | 2012-07-12 |
| MX2011012884A (en) | 2012-01-12 |
| CN101904814A (en) | 2010-12-08 |
| BRPI1010950A2 (en) | 2018-03-06 |
| CA2762918A1 (en) | 2010-12-09 |
| CN102159188A (en) | 2011-08-17 |
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